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Development of a Physiologically Based Pharmacokinetic Modelling Approach to Predict the Pharmacokinetics of Vancomycin in Critically Ill Septic Patients

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Abstract

Background and Objectives

Sepsis is characterised by an excessive release of inflammatory mediators substantially affecting body composition and physiology, which can be further affected by intensive care management. Consequently, drug pharmacokinetics can be substantially altered. This study aimed to extend a whole-body physiologically based pharmacokinetic (PBPK) model for healthy adults based on disease-related physiological changes of critically ill septic patients and to evaluate the accuracy of this PBPK model using vancomycin as a clinically relevant drug.

Methods

The literature was searched for relevant information on physiological changes in critically ill patients with sepsis, severe sepsis and septic shock. Consolidated information was incorporated into a validated PBPK vancomycin model for healthy adults. In addition, the model was further individualised based on patient data from a study including ten septic patients treated with intravenous vancomycin. Models were evaluated comparing predicted concentrations with observed patient concentration–time data.

Results

The literature-based PBPK model correctly predicted pharmacokinetic changes and observed plasma concentrations especially for the distribution phase as a result of a consideration of interstitial water accumulation. Incorporation of disease-related changes improved the model prediction from 55 to 88% within a threshold of 30% variability of predicted vs. observed concentrations. In particular, the consideration of individualised creatinine clearance data, which were highly variable in this patient population, had an influence on model performance.

Conclusion

PBPK modelling incorporating literature data and individual patient data is able to correctly predict vancomycin pharmacokinetics in septic patients. This study therefore provides essential key parameters for further development of PBPK models and dose optimisation strategies in critically ill patients with sepsis.

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Authors and Affiliations

  1. Department of Clinical Pharmacy, Institute of Pharmaceutical and Medical Chemistry, University of Muenster, Corrensstrasse 48, 48149, Muenster, Germany

    Christian Radke & Georg Hempel

  2. Department of Pharmacy, University Hospital of Muenster, Muenster, Germany

    Dagmar Horn

  3. Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital of Muenster, Muenster, Germany

    Christian Lanckohr & Björn Ellger

  4. Systems Pharmacology CV, Bayer Technology Services GmbH, Leverkusen, Germany

    Michaela Meyer & Thomas Eissing

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  1. Christian Radke
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Correspondence to Georg Hempel.

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This work was financially supported by a research grant from Bayer Technology Services GmbH as part of a PhD thesis of Christian Radke. The research grant was received by Georg Hempel (between 2012 and 2015).

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Michaela Meyer and Thomas Eissing were employed by Bayer Technology Services GmbH during the preparation of the manuscript and are potential stock holders of Bayer AG, the holding owning Bayer Technology Services GmbH. Dagmar Horn, Christian Lanckohr and Björn Ellger have no potential conflicts of interest to declare.

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Radke, C., Horn, D., Lanckohr, C. et al. Development of a Physiologically Based Pharmacokinetic Modelling Approach to Predict the Pharmacokinetics of Vancomycin in Critically Ill Septic Patients. Clin Pharmacokinet 56, 759–779 (2017). https://doi.org/10.1007/s40262-016-0475-3

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